Hydroxamic and carboxylic acid derivatives

ABSTRACT

Compounds having therapeutic utility are of formula (I) 
     B—X—(CH 2 ) n —CR 2 R 3 —CR 4 R 5 —COY  (I) 
     wherein  
     n=0-1;  
     X is S(O) 0-2 ;  
     Y is OR 1  or NHOH;  
     R 2  and R 4  are independently H or a group (optionally substituted with R 10 ) selected from C 1-6  alkyl, C 2-6  alkenyl, aryl, C 1-6 , alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkyl and C 1-6  alkyl-cycloalkyl; and  
     R 1 , R 3  and R 5  are independently H or C 1-6  alkyl;  
     provided that not more than two of R 2 , R 3 , R 4  and R 5  are H; or  
     any of CR 2 R 3 , CR 4 R 5  and CR 2 -CR 4  is a cycloalkyl or heterocycloalkyl ring optionally substituted with R 10  or a group (optionally substituted with R 10 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl and C 1-6  alkyl-heteroaryl;  
     B is heterocycloalkyl (optionally substituted by R 6  or R 7 ) bonded through carbon to X, or C 1-6  alkyl-heterocycloalkyl (optionally substituted with R 6  or R 7 ), or a group (substituted with R 6 ) selected from C 1-8  alkyl, C 2-6  alkenyl and C 2-6  alkynyl;  
     R 6  is N(R 7 ) 2 , OR 7 , COR 7 , C(═NOR 19 )R 7 , NR 7 R 8 , S(O) 0-2 R 9  or SO 2 N(R 7 ) 2 ;  
     R 7  is H or a group selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl and C 1-6  alkyl-heterocycloalkyl, wherein said group is optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 , and for each case of N(R 7 ) 2  the R 7  groups are the same or different or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 9 , COR 9 , SO 0-2 R 9 , CO 2 R 9 , OR 9 , CONR 1 R 9 , NR 1 R 9 , halogen, CN, SO 2 NR 1 R 9  or NO 2 ;  
     R 8  is COR 7 , CON(R 7 ) 2 , CO 2 R 9  or SO 2 R 9 ;  
     R 9  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl; and  
     R 10  is OR 7 , COR 8 , CO 2 R 1 , CON(R 7 ) 2 , NR 7 R 1 , S(O) 0-2 R 9 , SO 2 N(R 7 ) 2 , CN, halogen or cyclomidyl (optionally substituted with R 1 );  
     and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.

REFERENCE TO RELATED APPLICATION

[0001] This Application is a continuation-in-part of application Ser.No. 09/244,739, filed Feb. 5, 1999.

FIELD OF THE INVENTION

[0002] This invention relates to hydroxamic and carboxylic acidderivatives, and to their use in medicine.

BACKGROUND TO THE INVENTION

[0003] Metalloproteinases, including matrix metalloproteinase (MMP),(human fibroblast) collagenase, gelatinase and TNF convertase (TACE),and their modes of action, and also inhibitors thereof and theirclinical effects, are described in WO-A-9611209, WO-A-9712902 andWO-A-9719075, the contents of which are incorporated herein byreference. MMP inhibitors may also be useful in the inhibition of othermammalian metalloproteinases such as the adamalysin family (or ADAMs)whose members include TNF convertase (TACE) and ADAM-10, which can causethe release of TNFα from cells, and others, which have been demonstratedto be expressed by human articular cartilage cells and also involved inthe destruction of myelin basic protein, a phenomenon associated withmultiple sclerosis.

[0004] Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown, such ascollagenase, stromelysin and gelatinase, have been shown to inhibit therelease of TNF both in vitro and in vivo. See Gearing et al (1994),Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561;GB-A-2268934; and WO-A-9320047. All of these reported inhibitors containa hydroxamic acid zinc-binding group, as do the imidazole-substitutedcompounds disclosed in WO-A-9523790. Other compounds that inhibit MMPand/or TNF are described in WO-A-9513289, WO-A-9611209, WO-A-96035687,WO-A-96035711, WO-A-96035712 and WO-A-96035714.

[0005] WO-A-9834915 (published after the earliest priority date claimedherein) discloses compounds of formula I (below) wherein B isheterocycloalkyl (optionally substituted by R⁶ or R⁷) bonded throughcarbon to X.

[0006] WO-A-9839315 (published after the earliest priority date claimedherein) discloses compounds of formula I (below) wherein R⁴ is H and R⁵is unsubstituted C₁₋₆ alkyl, and B is C₁₋₈ alkyl optionally substitutedby OR⁷.

SUMMARY OF THE INVENTION

[0007] The invention encompasses compounds of formula (I), many of whichare novel, which are useful inhibitors of matrix metalloproteinasesand/or TNFα-mediated diseases, including degenerative diseases andcertain cancers.

[0008] Compounds according to the invention are of the general typerepresented by formula (I):

B—X—(CH₂)_(n)—CR²R³—CR⁴R⁵—COY   (I)

[0009] wherein

[0010] n=0-1;

[0011] X is S(O)₀₋₂;

[0012] Y is OR¹ or NHOH;

[0013] R² and R⁴ are independently H or a group (optionally substitutedwith R¹⁰ selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, heterocycloalkyl, C₁₋₆alkyl-heterocycloalkyl, cycloalkyl and C₁₋₆ alkyl-cycloalkyl; and

[0014] R¹, R³ and R⁵ are independently H or C₁₋₆ alkyl;

[0015] provided that not more than two of R², R³, R⁴ and R⁵ are H; or

[0016] any of CR²R³, CR⁴R⁵ and CR²—CR⁴ is a cycloalkyl orheterocycloalkyl ring optionally substituted with R¹⁰ or a group(optionally substituted with R¹⁰ selected from C₁₋₆ alkyl, aryl,C₁₋₆alkyl-aryl, heteroaryl and C₁₋₆ alkyl-heteroaryl;

[0017] B is heterocycloalkyl (optionally substituted by R⁶ or R⁷) bondedthrough carbon to X, or C₁₋₆ alkyl-heterocycloalkyl (optionallysubstituted with R⁶ or R⁷), or a group (substituted with R⁶) selectedfrom C₁₋₈ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;

[0018] R⁶is N(R⁷)₂, R⁷ COR⁷, C(═NOR⁹)R⁷, NR⁷R⁸, S(O)₀₋₂R⁹ or SO₂N(R⁷)₂;

[0019] R⁷ is H or a group selected from C₁₋₆alkyl, aryl, C₁₋₆alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl, wherein said group isoptionally substituted with R⁹, COR⁹, SO₀₋₂R⁹, CO₂R⁹, OR⁹, CONR¹R⁹,NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂, and for each case of N(R7)₂ the R⁷groups are the same or different or N(R⁷)₂ is heterocycloalkyloptionally substituted with R⁹, COR⁹, SO₀₋₂R⁹, CO₂R⁹, OR⁹, CONR¹R⁹,NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂;

[0020] R⁸ is COR⁷, CON(R⁷)₂, CO₂R⁹ or SO₂R⁹;

[0021] R⁹ is C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆alkyl-heteroaryl; and

[0022] R¹⁰ is OR⁷, COR⁷, CO₂R¹, CON(R⁷)₂, NR⁷R⁸, S(O)₀₋₂R⁹, SO₂N(R⁷)₂,CN, halogen or cycloimidyl (optionally substituted with R¹);

[0023] and the salts, solvates, hydrates, N-oxides, protected amino,protected carboxy and protected hydroxamic acid derivatives thereof.

[0024] Combinations of substituents and/or variables are onlypermissible if such combinations result in stable compounds.

DESCRIPTION OF THE INVENTION

[0025] Certain compounds of the invention are preferred. The followinggroups and variables are particularly preferred.

[0026] One group of compounds of the invention has the formula (I)wherein X, Y, n, R², R³, R⁴ and R⁵ are as defined above and B isoptionally substituted C₁₋₈ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl,especially an optionally substituted C₁₋₈ alkyl group, in particularethyl or propyl, especially propyl. Compounds of this type arepreferably substituted with R⁶, especially where R⁶ isOR^(1∂. Particular R) ⁷ groups are optionally substituted aryl orheteroaryl, especially, optionally substituted phenyl, pyridyl, furanylor thiophenyl, especially optionally substituted phenyl. R⁷ whensubstituted, is in particular substituted with R⁹, in particular phenyl,OR⁹, in particular OCH₃, F, Cl, Br, I or CN. Particularly preferredsubstituents are phenyl, OCH₃ or Cl.

[0027] Another particular group of compounds of the invention has theformula (I) wherein X, Y, n, R², R³, R⁴ and R⁵ are as defined above andB is an optionally substituted C₁₋₆ alkyl-heterocycloalkyl group.Especially preferred are those compounds wherein B the alkyl moiety in βis ethyl or propyl, especially ethyl, and the heterocycloalkyl moiety isoptionally substituted azetidinyl, pyrrolidinyl or piperidinyl,especially optionally substituted pyrrolidinyl. Compounds of this typeare preferably substituted with R⁷, especially when R⁷ is optionallysubstituted aryl or heteroaryl. Particular R⁷ groups are optionallysubstituted phenyl, pyridyl, furanyl or thiophenyl, especiallyoptionally substituted phenyl. R⁷ when substituted, is in particularsubstituted with OR⁹, in particular OCH₃, F, Cl, Br, I, NO₂ or CN.

[0028] A further useful group of compounds has the formula (I) whereinX, Y, n, R², R³, R⁴ and R⁵ are as defined above and B is optionallysubstituted heterocycloalkyl bonded through carbon to X, in particularoptionally substituted azetidinyl, pyrrolidinyl or piperidinyl,especially piperidinyl. Compounds of this type are preferablysubstituted with R⁷, especially when R⁷ is optionally substituted arylor heteroaryl. Particular R⁷ groups are optionally substituted phenyl,pyridyl, furanyl or thiophenyl, especially optionally substitutedphenyl. R⁷ when substituted, is in particular substituted with OR⁹, inparticular OCH₃, F, Cl, Br, I, NO₂ or CN. In compounds of the inventionwhen B is optionally substituted heterocycloalkyl bonded through carbonto X and CR⁴R⁵ is preferably an optionally substituted heterocycloalkylgroup, then the CR⁴R⁵ group is a saturated heterocyclic moiety havingfrom two to six carbon atoms and one or more heteroatoms from the groupO or S (or oxidised versions thereof) which may be optionally benzofusedat any available position.

[0029] In general in compounds of the invention the most preferredcompounds are those wherein any one or more of the following may apply:

[0030] X is SO₂;

[0031] Y is NHOH; and

[0032] n is 0.

[0033] R² or R⁴ is preferably optionally substituted C₁₋₆ alkyl, C₁₋₆alkyl-heteroaryl, or C₁₋₆ alkyl-heterocycloalkyl. In compounds of thistype, R⁴ and R⁵, or R² and R⁴, preferably form an optionally substitutedcycloalkyl or heterocycloalkyl group, in particular, a cyclobutyl,cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl orpiperidinyl group, especially cyclobutyl, cyclopentyl or cyclohexyl. Inanother preference, the heterocycloalkyl group represented by R⁴ and R⁵together is optionally substituted tetrahydropyranyl.

[0034] The compounds of the Examples are particularly preferred.

[0035] It will be appreciated that the compounds according to theinvention can contain one or more asymmetrically substituted carbonatoms. The presence of one-or more of these asymmetric centres in acompound of formula (I) can give rise to stereoisomers, and in each casethe invention is to be understood to extend to all such stereoisomers,including enantiomers and diastereomers, and mixtures including racemicmixtures thereof.

[0036] It will further be appreciated that the compounds according tothe invention may contain an oxime. This oxime can give rise togeometrical isomers, and in each case the invention is to be understoodto extend to all such isomers and mixtures thereof.

[0037] As used in this specification, alone or in combination, the term“C₁₋₆alkyl” refers to straight or branched chain alkyl moiety havingfrom one to six carbon atoms, including for example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

[0038] The term “C₁₋₈alkyl” refers to straight or branched chain alkylmoiety having from one to eight carbon atoms, including for example,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl,octyl and the like.

[0039] The term “C₂₋₆ alkenyl” refers to a straight or branched chainalkyl moiety having two to six carbon atoms and having in addition onedouble bond, of either E or Z stereochemistry where applicable. Thisterm would include for example, vinyl, 1-propenyl, 1- and 2-butenyl,2-methyl-2-propenyl etc.

[0040] The term “C₂₋₆ alkynyl” refers to a straight or branched chainalkyl moiety having two to six carbon atoms and having in addition onetriple bond. This term would include for example, ethynyl, 1-propynyl,1- and 2-butynyl, 1- methyl-2-butynyl etc.

[0041] The term “cycloalkyl” refers to a saturated alicyclic moietyhaving from three to six carbon atoms and includes for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0042] The term “heterocycloalkyl” refers to a saturated heterocyclicmoiety having from two to six carbon atoms and one or more heteroatomfrom the group N, O, S (or oxidised versions thereof) which may beoptionally benzofused at any available position. This includes forexample azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, benzodioxole and the like.

[0043] The term “aryl” refers to an aromatic carbocyclic radical havinga single ring or two condensed rings. This term includes, for example,phenyl and naphthyl.

[0044] The term “heteroaryl” refers to aromatic ring systems of five toten atoms of which at least one atom is selected from O, N and S, andincludes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl andthe like.

[0045] The term “halogen” means fluorine, chlorine, bromine or iodine.

[0046] The term “benzofused” refers to the addition of a benzene ringsharing a common bond with the defined ring system.

[0047] The term “cycloimidyl” refers to a saturated ring of five to tenatoms containing the atom sequence —C(═O)NC(═O)—. The ring may beoptionally benzofused at any available position. Examples includesuccinimidoyl, phthalimidoyl and hydantoinyl.

[0048] The term “optionally substituted” means optionally susbsitutedwith one or more of the groups specified, at any available position orpositions.

[0049] The terms “protected amino”, “protected carboxy” and “protectedhydroxamic acid” mean amino, carboxy and hydroxamic acid groups whichcan be protected in a manner familiar to those skilled in the art. Forexample, an amino group can be protected by a benzyloxycarbonyl,tert-butoxycarbonyl, acetyl or like group, or may be in the form of aphthalimido or like group. A carboxyl group can be protected in the formof a readily-cleavable ester such as the methyl, ethyl, benzyl ortert-butyl ester. A hydroxamic acid may be protected as either N or0-substituted derivatives, such as O-benzyl orO-tert-butyldimethylsilyl.

[0050] Salts of compounds of formula (I) includepharmaceutically-acceptable salts, for example acid addition saltsderived from inorganic or organic acids, such as hydrochlorides,hydrobromides, p-toluenesulphonates, phosphates, sulphates,perchlorates, acetates, trifluoroacetates, propionates, citrates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

[0051] Salts may also be formed with bases. Such salts include saltsderived from inorganic or organic bases, for example alkali metal saltssuch as magnesium or calcium salts, and organic amine salts such asmorpholine, piperidine, dimethylamine or diethylamine salts.

[0052] When the “protected carboxy” group in compounds of the inventionis an esterified carboxyl group, it may be a metabolically-labile esterof formula CO₂R¹¹ where R¹¹ may be an ethyl, benzyl, phenethyl,phenylpropyl, α- or β-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl,2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl,2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl orpivaloylmethyl group.

[0053] Compounds of the general formula (I) may be prepared by anysuitable method known in the art and/or by the following processes.

[0054] It will be appreciated that, where a particular stereoisomer offormula (I) is required, the synthetic processes described herein may beused with the appropriate homochiral starting material and/or isomersmaybe resolved from mixtures using conventional separation techniques(e.g. HPLC).

[0055] The compounds according to the invention may be prepared by thefollowing process. In the description and formulae below the groups R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R¹, R⁹, R¹⁰, R¹¹, B, X and Y are as definedabove, except where otherwise indicated. It will be appreciated thatfunctional groups, such as amino, hydroxyl or carboxyl groups, presentin the various compounds described below, and which it is desired toretain, may need to be in protected form before any reaction isinitiated. In such instances, removal of the protecting group may be thefinal step in a particular reaction. Suitable protecting groups for suchfunctionality will be apparent to those skilled in the art. For specificdetails see Greene et al, “Protective Groups in Organic Synthesis”,Wiley Interscience.

[0056] A process for preparing compounds of general formula (I)comprises reacting a compound of formula B—SH (II) with (a) analkylating agent of formula Z—(CH₂)_(n)—CR²R³—CR⁴R⁵—COY (III) (wherein Zrepresents a suitable leaving group e.g. a halogen such as bromine, oran alkylsulphonate ester such as methanesulphonate), or (b) (when n=0and R⁵=H) an acrylate of formula CR²R³═CR⁴—COY (IV) or (c) a lactone ofthe formula (V)

[0057] An alternative process for preparing compounds of formula (I)involves reacting a compound of formula BSQ (XII), where Q is a suitablelabile group, such as acetyl, in the presence of a strong base such ashexamethyldisilazide with (a) an alkylating agent of formula (III) or(b) an acrylate of formula (IV).

[0058] A further alternative process for preparing compounds of formula(I) involves reacting a compound of formula B—Z (VI) with a compound offormula Q—S—(CH₂)_(n)CR²R³CR⁴R⁵COY (VII), where Z is defined above and Qis a suitable labile group, such as acetyl, in the presence of a strongbase such as hexamethyldisilazide in an inert solvent such astetrahydrofuran. Compounds of formula (VII) may be prepared by reactionof a compound of formula QSH (VIII) with a compound (III), (IV) or (V)as defined above, optionally in the presence of an organic or inorganicbase.

[0059] Alkylating agents of formula (III) can be obtained in chiral orracemic form. Many of these derivatives can be readily obtained fromcommercially available starting materials using methods known to thoseskilled in the art (e.g. see WO-A-9005719).

[0060] Acrylates of formula (IV) may be prepared by the condensation ofa carbonyl compound of the form R⁴CH₂COY (IX) with ketones or aldehydesof formula R²COR³ (X). This reaction may be performed under a variety ofconditions known to those skilled in the art, for example under theaction of a strong base such as lithium dilsopropylamide in an inertsolvent such as tetrahydrofuran, to give an intermediate alcohol of theform R²C(OH)R³CHR⁴COY (XI). These alcohols (XI) may or may not beisolated: dehydration may occur in situ or be performed separately underappropriate conditions such as aqueous acid to give the desired acrylate(IV).

[0061] Lactones of formula (V) may be prepared by chemistry known tothose skilled in the art. For example see EP-A-0780386.

[0062] Many compounds of formula (II) and (VII) are availablecommercially, or may be prepared from compounds of the form B—Z (VI) bystandard methods (for example, see WO-A-9611209).

[0063] Many compounds of formula (VIII), (VI), (IX) and (X) areavailable commercially,: or may be prepared from compounds availablecommercially by standard methods. Other substituents described by R²,R⁴, or R⁶ or can be introduced by standard chemical transformationsknown to those skilled in the art.

[0064] Compounds of formula (I) may also be prepared by interconversionof other compounds of formula (I). Thus, for example, a compound offormula (I) wherein R² is a C₁₋₆ alkyl group may be prepared byhydrogenation (using palladium on carbon in suitable solvent, such as analcohol, e.g. ethanol) of a compound of formula (I) wherein R² is a C₂₋₆alkenyl group. Further, a compound of formula (I) wherein X is S(O)₁₋₂may be prepared by oxidation of a compound of formula (I) wherein X is Sfor example, using Oxone®, in a suitable solvent, such as methanol.Compounds of formula (I) wherein B is (CH₂)₁₋₈OR⁷ (where R⁷ is aryl orheteroaryl) may be prepared, for example, by activating a correspondingcompound of formula (I), wherein B is (CH₂)₁₋₈OH, with an appropriateactivating agent, such as triphenylphosphine or diethylazodicarboxylate,followed by addition of R⁷OH, using an inert solvent, such astetrahydrofuran.

[0065] Esters of formula (I) may be converted to carboxylic acids offormula (I) using methods known to those skilled in the art, such ashydrolysis in the presence of an aqueous base, such as lithiumhydroxide, in a suitable alcoholic solvent, such as methanol. Carboxylicacids of general formula (I) (Y═OH) may be converted to other compoundsof formula (I) such as esters (Y═OR¹ ) or hydroxamic acids (Y═NHOH)using methods known to those skilled in the art, or as described in theExamples, hereinafter.

[0066] Compounds of formula (I) may also be prepared by interconversionof other compounds of formula (I). Thus, for example, a compound offormula (I) wherein R² is a C₁₋₆alkyl group may be prepared byhydrogenation (using palladium on carbon in suitable solvent, such as analcohol, e.g. ethanol) of a compound of formula (I) wherein R² is a C₂₋₆alkenyl group. Further, a compound of formula (I) wherein X is S(O)₁₋₂may be prepared by oxidation of a compound of formula (I) wherein X isS.

[0067] Carboxylic acids of general formula (I) (Y═OH) may be convertedto other compounds of formula (I) such as esters (Y═OR¹ ) or hydroxamicacids (Y═NHOH) using methods known to those skilled in the art.

[0068] Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallization, or by formation of a salt if appropriate or possibleunder the circumstances.

[0069] The compounds according to the invention exhibit in vitroinhibiting activities with respect to the stromelysins, collagenases andgelatinases. Compounds according to the. invention may also exhibit invitro inhibition of membrane shedding events known to be mediated bymetalloproteinases, for example, α-APP, ACE, TGF-α, TNF-α, Fas ligand,TNFR-I, TNFR-II, CD30, II-6R, CD43, CD44, CD16-I, CD16-II, Folatereceptor, CD23, or IL-1RII.

[0070] The activity and selectivity of the compounds may be determinedby use of the appropriate enzyme inhibition test, for example asdescribed in Examples A-M of WO-A-9805635, by the assay for theinhibition of CD23 shedding described in PCT/GB98/03395, or by thefollowing assay of TNF RI shedding.

[0071] The potency of the compounds of general formula (I) to act asinhibitors of the production of TNF RI is determined using the followingprocedure. A 100 μM solution of the inhibitor being tested or dilutionsthereof is incubated at 37° C. in an atmosphere of 5% CO₂ withperipheral blood mononuclear cells (PBMC). PBMC are isolated from buffycoats by standard procedures using Ficoll. A 100 μM solution of theinhibitor being tested or dilutions thereof is incubated for 22 hours at37° C. in an atmosphere of 5% CO₂ with 1×10⁶/ml PBMC stimulated withLPS. The cells are centrifuged down and the supernatant is assayed forTNF RI using a commercially available ELISA kit (R & D Systems). Theactivity in the presence of 0.1 mM inhibitor or dilutions thereof iscompared to activity in a control devoid of inhibitor and resultsreported as that inhibitor concentration effecting 50% inhibition of theproduction of TNF RI.

[0072] This invention also relates to a method of treatment for patients(including man and/or mammalian animals raised in the dairy, meat or furindustries or as pets) suffering from disorders or diseases which can beattributed to stromelysin as previously described, and morespecifically, a method of treatment involving the administration of thematrix metalloproteinase inhibitors of formula (I) as the activeconstituents.

[0073] Accordingly, the compounds of formula (I) can be used among otherthings in the treatment of osteoarthritis and rheumatoid arthritis, andin diseases and indications resulting from the over-expression of thesematrix metalloproteinases such as found in certain metastatic tumourcell lines.

[0074] As mentioned above, compounds of formula (I) are useful in humanor veterinary medicine since they are active as inhibitors of TNF andMMPs. Accordingly in another aspect, this invention concerns:

[0075] a method of management (by which is meant treatment ofprophylaxis) of disease or conditions mediated by TNF and/or MMPs inmammals, in particular in humans, which method comprises administeringto the mammal an effective, amount of a compound of formula (I) above,or a pharmaceutically acceptable salt thereof; and

[0076] a compound of formula (I) for use in human or veterinarymedicine, particularly in the management (by which is meant treatment orprophylaxis) of diseases or conditions mediated by TNF and/or MMPs; and

[0077] the use of a compound of formula (I) in the preparation of anagent for the management (by which is meant treatment or prophylaxis) ofdiseases or conditions mediated by TNF and/or MMPs.

[0078] The disease or conditions referred to above include inflammatorydiseases, autoimmune diseases, cancer, cardiovascular diseases, diseasesinvolving tissue breakdown such as rheumatoid arthritis, osteoarthritis,osteoporosis, neurodegeneration, Alzheimer's disease, stroke,vasculitis, Crohn's disease, ulcerative colitis, multiple sclerosis,periodontitis, gingivitis and those involving tissue breakdown such asbone resorption, haemorrhage, coagulation, acute phase response,cachexia and anorexia, acute infections, HIV infections, fever, shockstates, graft versus host reactions, dermatological conditions, surgicalwound healing, psoriasis, atopic dermatitis, epidermolysis bullosa,tumour growth, angiogenesis and invasion by secondary metastases,ophthalmological disease, retinopathy, corneal ulceration, reperfusioninjury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis,eczema, anaphylaxis, restenosis, congestive heart failure,endometriosis, atherosclerosis, endosclerosis and aspirin-independentanti-thrombosis.

[0079] Compounds of formula (I) may also be useful in the treatment ofpelvic inflammatory disease (PID), age-related macular degeneration andcancer-induced bone resorption. Further, they can be used in thetreatment of lung diseases, e.g. selected from cystic fibrosis, adultrespiratory distress syndrome (ARDS), emphysema, bronchitisobliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis(PIF), diffuse alveolar damage, pulmonary Langerhan's cellgranulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronicobstructive pulmonary disease (COPD).

[0080] For the treatment of rheumatoid arthritis, osteoarthritis, and indiseases and indications resulting from the over-expression of matrixmetalloendoproteinases such as found in certain metastatic tumour celllines or other diseases mediated by the matrix metalloendoproteinases orincreased TNF production, the compounds of formula (I) may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, cattle, sheep, dogs, cats etc, the compounds of the inventionare effective in the treatment of humans.

[0081] The pharmaceutical composition containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in the gastointestinaltract and thereby provide a sustained action over a longer period. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate may be employed. They may also be coated by the techniquesdescribed in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, toform osmotic therapeutic tablets for control release.

[0082] Formulations for oral use may also be presented as hard gelatincapsules where in the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0083] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such a polyoxyethylene with partial esters derived from fattyacids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives,. for example ethyl, or n-propyl, p-hydroxybenzoate, oneor more colouring agents, one or more flavouring agents, and one or moresweetening agents, such as sucrose or saccharin.

[0084] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0085] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified, for example sweetening,flavouring and colouring agents, may also be present.

[0086] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally- occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavouring agents.

[0087] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand colouring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be ina sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0088] The compounds of formula (I) may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0089] For topical use, creams, ointments, jellies, solutions orsuspensions, etc containing the compounds of Formula (I) are employed.For the purposes of this specification, topical application includesmouth washes and gargles.

[0090] Dosage levels of the order of from about 0.05 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove- indicated conditions (about 2.5 mg to about 7 g per patient perday). For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day (about 0.5 mg to about 3.5 g per patient perday).

[0091] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of humansmay vary from about 5 to about 95% of the total composition. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofactive ingredient.

[0092] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

[0093] The following Examples illustrate the invention. The followingabbreviations are used:

[0094] RT=Room Temperature THF=Tetrahydrofuran h=Hour

[0095] Intermediate 1 2,7-Dioxaspiro[3.5]nonan-1-one

[0096] Was prepared according to the procedure outlined in EP-A-0780386,as a colourless oil (5.2 g).

[0097] Intermediate 2 1-Bromo-3-(4-chlorophenoxy)propane

[0098] Sodium hydride (3.3 g, 60% dispersion in oil) was added to asolution of 4-chlorophenol (9.0 g) in DMF (30 ml) at 0° C. and themixture was stirred for 30 min, then 1,3-dibromopropare (22.5 g, 1.5 eq)was added. The mixture was stirred at room temperature for 18 h, thenadded to water (300 ml) and extracted with ether. The solvent was washedwith 5% NaOH and brine, dried over MgSO₄ and evaporated and the residuepurified on silica gel, eluting with 1:1 ether/hexane, to give the titlecompound (13.5 g) as a colourless oil.

[0099] TLC R_(f) 0.73 (ether).

[0100] Intermediate 3 1-Acetylsulfanyl-3-(4-chlorophenoxy)propane

[0101] A solution of Intermediate 2 (6.0 g) in DMF (50 ml) was treatedwith potassium thioacetate (5.7 g) at room temperature for 3 h, then thebrown solution was added to 5% sodium bicarbonate solution and extractedwith ether (3×200 ml). The solvent was washed with water (200 ml) andbrine, dried over MgSO₄ and evaporated to give the title compound (5.50g) as a beige solid.

[0102] TLC R_(f) 0.54 (ether).

[0103] The following compound was prepared in a similar manner:

[0104] Intermediate 4 Thioacetic acid S-(3-phenoxypropyl)ester

[0105] Prepared in the same manner as Intermediate 3 from3-phenoxypropyl bromide (8 ml) and potassium thioacetate (7.01 g) togive the title compound (10.35 g) as an orange oil.

[0106] TLC R_(f) 0.74 (1:1 hexane-ethyl acetate)

[0107] Intermediate 5 Methyl 4-iodomethyl-tetrahydropyran-4-carboxylate

[0108] To a stirred solution of methyl tetrahydropyran-4-carboxylate(3.00 g) in anhydrous THF (50 ml) under nitrogen at 0° C. was added asolution of lithium di-isopropylamide (2.0 M, 10.9 ml). After 30minutes, diiodomethane (8.36 g) was added and the mixture was allowed towarm up to RT and then stirred for 1 h. The mixture was poured ontowater (50 ml) and extracted with ether (3×40 ml). The combined etherlayers were washed with water (2×20 ml), aqueous hydrochloric acid (2 M,20 ml), water (20 ml) and brine (20 ml), dried (MgSO₄) and evaporatedunder reduced pressure. The residue was purified on silica gel, elutingwith 3:1 hexane/ether, to give the title compound (3.11 g) as acolourless oil.

[0109] TLC R_(f) 0.26 (3:1 hexane/ether)

[0110] The following compound was prepared in a similar manner:

[0111] Intermediate 6 Methyl 1-iodomethylcyclohexanecarboxylate

[0112] Prepared in the same manner as Intermediate 5 from methylcyclohexane-carboxylate (0.32 ml) and diiodomethane (0.18 ml) to yieldthe title compound as a pale yellow oil (0.62 g, 97%)

[0113] TLC R_(f) 0.84 (1:1 hexane/diethyl ether)

[0114] Intermediate 7 Methyl4-Acetylsulfanylmethyl-tetrahydropyran-4-carboxylate

[0115] A solution of Intermediate 4 (3.05 g) in DMF (20 ml) was treatedwith potassium thioacetate (1.47 g) at room temperature for 18 h, thenthe brown solution was added to 5% sodium bicarbonate solution andextacted with ether (3×200 ml). The solvent was washed with water (200ml) and brine, dried over MgSO₄ and evaporated to give the titlecompound (2.42 g) as a white solid.

[0116] TLC R_(f) 0.44 (1: 1 hexane/ether).

[0117] Intermediate 8 1-Acetylsulfanylmethyl-cyclobutanecarboxylic acidethyl ester

[0118] n-Butyllithium (49.8 ml of a 1.6 N solution in hexanes) was addedgradually to a solution of diisopropylamine (11.2 ml) in tetrahydrofuran(90 ml) cooled in an acetone-cardice bath under an atmosphere ofnitrogen. After stirring for 30 minutes, ethyl cyclobutanecarboxylate(10 ml) was added. The mixture was stirred for a further 30 minutesbefore addition of diiodomethane (6.4 ml), and then for 3 hours, duringwhich it warmed to room temperature. It was quenched with water (30 ml)and the tetrahydrofuran evaporated in vacuo. The residue was partitionedbetween ethyl acetate (100 ml) and water (100 ml). The aqueous wasextracted with ethyl acetate (100 ml). The combined organics were dried(MgSO₄) and the solvent removed in vacuo to give a brown oil which wasdissolved in N,N-dimethylformamide (40 ml) and added to a suspension ofpotassium thioacetate (8.3 g) in N,N-dimethylformamide (40 ml) at roomtemperature. The mixture was stirred for 18 hours before evaporation ofthe solvent in vacuo. The residue was partitioned between ethyl acetate(100 ml) and water (100 ml). The organics were washed with water (100ml), dried (MgSO₄) and the solvent removed in vacuo to give the titlecompound (13.5 g) as a brown oil.

[0119] TLC R_(f) 0.59 (2:1 heptane-ethyl acetate)

[0120] Intermediate 9 [1-(4-Nitro-phenyl)-piperidin-4-yl]-methanol

[0121] Lithium aluminium hydride was added gradually to a solution ofethyl 1-4(nitrophenyl)-4-piperidine carboxylate (2.5 g) in TBF (30 ml)cooled in an ice bath. The mixture was stirred for 18 h at roomtemperature before being quenched with water (1 ml), 15% aqueous sodiumhydroxide (1 ml) and water (3 ml), filtered and evaporated under reducedpressure. The residue was partitioned between ethyl acetate (30 ml) andwater (20 ml) washed with water (20 ml), dried (MgSO₄), evaporated andthe residue purified by chromatography on silica, eluting with 3%methanol in dichloromethane, to give the title compound (0.95 g) as ayellow solid.

[0122] TLC R_(f) 0.27 (3% methanol in dichloromethane)

[0123] Intermediate 10 3-(2-Iodo-ethyl)-1-(4-nitro-phenyl)-pyrrolidine

[0124] A mixture of iodine (1.12 g) and triphenylphosphine (1.16 g) intoluene (20 ml) was stirred for 15 minutes before addition ofIntermediate 9 (951 mg). The mixture was heated to reflux for 6 hours.After cooling to room temperature, the mixture was partitioned betweenwater (20 ml) and ether (20 ml). The organics were washed with water(4×20 ml), aqueous sodium bicarbonate (20 ml), and brine (15 ml) beforebeing dried (MgSO4) evaporated and the residue purified bychromatography on silica, eluted with 20% ethyl acetate in hexane, togive the title compound (435 mg) as a orange solid.

[0125] TLC R_(f) 0.55 (30% ethyl acetate in hexane)

[0126] Intermediate 11 4-Hydroxypiperidine-1-carboxylic acid tert-butylester

[0127] Di-tert-butyl dicarbonate (20.5 g) was added to an ice-coldsolution of 4-hydroxypiperidine (10.0 g) in dichloromethane (150 ml),followed by the dropwise addition of triethylamine (27.5 ml). Thereaction was stirred for 1 h in the ice bath and then at roomtemperature for a further 20 h. The dichloromethane solution was thenwashed with water (80 ml, then 40 ml), 1.0 M hydrochloric acid (220 ml),water (40 ml), saturated sodium bicarbonate solution (30 ml), dried(MgSO₄) and evaporated under reduced pressure to give the title compoundas a colouless oil, which crystallised on standing (18.9 g, 100%).

[0128] TLC R_(f) 0.40 (5% methanol/dichloromethane)

[0129] Intermediate 12 4-(Acetylsulfanyl)piperidine-1-carboxylic acidtert-butyl ester

[0130] Triphenylphosphine (7.37 g) and Intermediate 11 (4.71 g) weredissolved in tetrahydrofuran (40 ml), under a nitrogen atmosphere, andcooled to −78° C. Diethyl azodicarboxylate (4.42 ml) was added viasyringe, followed by thiolacetic acid (2.17 ml). The reaction was thenstirred for 18 h, slowly warming to room temperature. The reaction wasreduced in vacuo and the residue redissolved in ethyl acetate (1.50 ml)and washed with saturated sodium bicarbonate solution (3×20 ml), water(2×20 ml) and saturated brine (20 ml). The organic phase was then dried(Na₂SO₄), and diluted with hexane (150-200 ml). The resultantprecipitate was removed by filtration, and the filtrate evaporated underreduced pressure. The pale green residue was then purified by silica gelcolumn chromatography with 1% methanol in dichloromethane as eluent toyield the title compound as a colourless oil (0.99 g, 16%).

[0131] TLC R_(f) 0.23 (1% methanol/dichloromethane)

Example 14-((3-(4-Chlorophenoxy)propylsulfanyl)methyl)-tetrahydropyran-4-carboxylicAcid

[0132] A solution of Intermediate 3 (0.80 g) in methanol was treatedwith a solution of sodium hexamethyldisilazide (1 M in THF, 3.3 ml) at0° C. and the resulting mixture was stirred for 2 h, then a solution ofIntermediate 1 (460 mg) in methanol was added. The mixture was stirredfor 18 h, then evaporated and the residue dissolved in water and washedwith diethyl ether. The aqueous phase was acidified with citric acid andextracted with dichloromethane; the organic layer was then washed withbrine, dried over MgSO₄ and evaporated to give the title compound (0.12g) as a colourless oil.

[0133] TLC R_(f) 0.54 (ether)

Example 2 Methyl4-(3-Hydroxypropylsulfanylmethyl)tetrahydropyran-4-carboxylate

[0134] To a stirred solution of Intermediate 7 (2.50 g) in methanol (100ml) under nitrogen at 0° C. was added a solution of sodiumhexamethyldisilazide (1M in THF, 11.3 ml) and the resulting mixture wasstirred for 10 mins, then a solution of 3-bromopropanol (1.5 g) wasadded. The mixture was stirred for 6 h, then evaporated and the residuetreated with water (100 ml) and extracted with dichloromethane (4×50ml). The combined dichloromethane extracts were washed with water (2×50ml), brine (50 ml), dried over MgSO₄ and evaporated. The residue waspurified on silica gel eluting with 2:1 ethyl acetate/hexane, to givethe title compound (2.41 g) as a colourless oil.

[0135] TLC R_(f) 0.26 (2:1 ethyl acetate/hexane).

[0136] The following compounds were prepared in a similar manner:

Example 3 2-(3-Phenoxypropylsulfanyl)cyclopentanecarboxylic acid methylester

[0137] Prepared in the same manner as Example 2 from Intermediate 4 (199mg) and methyl 1-cyclopentene-1-carboxylate (0.116 ml) to give, afterchromatography on silica, eluted with 1:1 hexane-dichloromethanefollowed by 1:3hexane-dichloromethane, the title compound (204 mg) as acolourless oil.

[0138] TLC R_(f) 0.31 (1:1 hexane-ethyl acetate)

[0139] MS 295 (MH⁺)

Example 41-{2-[1-(4-Nitrophenyl)pyrrolidin-3-yl]ethylsulfanylmethyl}-cyclobutanecarboxylicacid ethyl ester

[0140] Prepared in the same manner as Example 2 from Intermediate 8(0.15 g) and Intermediate 10 (0.21 g) to give the title compound (240mg) as an orange solid.

[0141] TLC R_(f) 0.47 (30% ethyl acetate in hexane)

[0142] MS 393 (MH⁺)

Example 5 Methyl4-((3-(4-Methoxyphenoxy)propylsulfanyl)methyl)-tetrahydropyran-4-carboxylate

[0143] To a stirred solution of Example 2 (500 mg) andtriphenylphosphine (528 mg) in dry THF (25 ml) at 0° C. under nitrogen,was added diethylazodicarboxylate (351 mg). After 5 min a solution of4-methoxyphenol (250 mg) in THF was added. The mixture was stirred for 2h with the temperature rising to RT, then poured into ether (100 ml) andwashed with water (2×25 ml), sodium hydroxide solution (1M; 25 ml),brine (25 ml) and dried over MgSO₄. Evaporation and purification onsilica gel eluting with 2:1 hexane/ethyl acetate, gave the titlecompound (415 mg) as a colourless oil.

[0144] TLC R_(f) 0.25 (2:1 hexane/ethyl acetate).

[0145] Similarly prepared were:

Example 6 Methyl4-((3-(4-Phenylphenoxy)propylsulfanyl)methyl)-tetrahydropyran-4-carboxylate

[0146] From Example 2 (500 mg) and 4-phenylphenol (343 mg) as a whitesolid (298 mg).

[0147] TLC R_(f) 0.45 (2:1 hexane/ethyl acetate).

Example 7 Methyl 4-((3-(3-Pyridyloxy)propylsulfanyl)methyl)tetrahydropyran-4-carboxylate

[0148] From Example 2 (500 mg) and 3-hydroxypyridine (191 mg) as acolourless oil (360 mg).

[0149] TLC R_(f) 0.19 (2:1 ethyl acetate/hexane).

Example 8 Methyl4-((3-(4-Methoxyphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylate

[0150] To a stirred solution of Example 5 (400 mg) in methanol (10 ml)at RT was added a solution of Oxone (1.04 g) in water (20 ml). Stirringwas continued for 18 h before diluting with water (50 ml) and extractingwith dichloromethane (4×25 ml). The combined organic layers were washedwith water (25 ml), brine (25 ml), dried over MgSO₄ and evaporated togive the title compound (385 mg) as a colourless oil.

[0151] TLC R_(f) 0.33 (2:1 ethyl acetate/hexane).

[0152] Similarly prepared were:

Example 9 Methyl4-((3-(4-Phenylphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylate

[0153] From Example 6 (290 mg) as a white solid (303 mg).

[0154] TLC R_(f) 0.33 (2:1 ethyl acetate/hexane).

Example 10 Methyl4-((3-(3-Pyridyloxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylate

[0155] From Example 7 (325 mg) as a colourless oil (350 mg).

[0156] TLC R_(f) 0.15 (ethyl acetate).

Example 111-{2-[1-(4-Nitrophenyl)pyrrolidin-3-yl]-ethanesulfonylmethyl}-cyclobutanecarboxylicacid ethyl ester

[0157] Prepared in the same manner as Example 8 from Example 4 (0.24 g)and oxone (0.56 g) to give, after chromatography on silica eluted with2:1 hexane-ethyl acetate, the title compound (60 mg) as a white solid.

[0158] TLC R_(f) 0.29 (1:1 hexane-ethyl acetate)

[0159] MS 425 (MH⁺)

Example 12 2-(3-Phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acidmethyl ester

[0160] Prepared in the same manner as Example 8 from Example 3 (202 mg)and oxone (613 mg) to give, after chromatography on silica, eluted with30% hexane in ether, the title compound (163 mg) as a colourless gum.

[0161] TLC R_(f) 0.49 (30% hexane in ether)

[0162] MS 327 (MH⁺)

Example 134-((3-(4-Chlorophenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylicAcid

[0163] Oxone (0.42 g) was added to a solution of Example 1 (0.12 g) inmethanol (10 ml) and water (5 ml) at room temperature and the mixturewas stirred for 3 h. The mixture was then evaporated to half volume,diluted with water (5 ml) and extracted with dichloromethane (2×20 ml).The organic layer was then washed with brine, dried over MgSO₄ andevaporated and the residue purified by flash column chromatography onsilica gel, eluting with ethyl acetate/acetic acid (99:1) to give thetitle compound (70 mg) as a white solid.

[0164] TLC R_(f) 0.70

[0165] MS 376 (M⁺)

Example 144-((3-(4-Methoxyphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylicAcid

[0166] To a stirred solution of Example 8 (380 mg) in methanol (30 ml)was added a solution of lithium hydroxide (206 mg) in water (10 ml). Themixture was refluxed for 1.5 h, cooled to RT and diluted with water (50ml). The aqueous mixture was washed with ether (2×20 ml), acidified (2MHCl, pH1) and extracted with ethyl acetate (5×25 ml). The combined ethylacetate fractions were washed with water (2×20 ml), brine (20 ml), driedover MgSO₄ and evaporated to give the title compound (266 mg) as a whitesolid.

[0167] TLC R_(f) 0.10 (ethyl acetate)

[0168] MS 372 (M⁺)

[0169] Similarly prepared were:

Example 154-((3-(4-Phenylphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylicAcid

[0170] From Example 9 (300 mg) as a white solid (203 mg).

[0171] TLC R_(f) 0.15 (ethyl acetate)

[0172] MS 418 (M⁺)

Example 16 4-((3-(3-Pyridyloxy)propylsulfonyl)methyl)tetrahydropyran 4carboxylate

[0173] From Example 10 (325 mg) as a white solid (103 mg).

[0174] TLC R_(f) 0.10 (ethyl acetate)

[0175] MS 343 (M⁺)

Example 171-{2-[1-(4-Nitrophenyl)pyrrolidin-3-yl]ethanesulfonylmethyl}-cyclobutanecarboxylicacid

[0176] Prepared in the same manner as Example 14 from Example 11 (60 mg)and lithium hydroxide monohydrate (29 mg) to give Example 17 (75 mg) asa yellow solid.

[0177] TLC R_(f) 0.44 (5% methanol in dichloromethane)

[0178] MS 397 (MH⁺)

Example 18 2-(3-Phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid

[0179] Prepared in the same manner as Example 14 from Example 12 (163mg) and lithium hydroxide (105 mg) to give the title compound (134 mg)as a white solid.

[0180] TLC R_(f) 0.34 (1:1 hexane-ethyl acetate+1% acetic acid)

[0181] MS 311 (M-H)

Example 194-(1-Methoxycarbonylcyclohexylmethylsulfanyl)piperidine-1-carboxylicacid tert-butyl ester

[0182] Intermediate 6 (0.50 g) and Intermediate 12 (0.46 g) werecombined in anhydrous methanol, degassed, cooled to −10° C., and treatedwith sodium bis(trimethylsilyl)amide (1.78 ml, as a 1.0 M solution intetrahydrofuran), and the mixture stirred for 18 h, slowly warming toroom temperature. The reaction was then reduced in vacuo, diluted withwater (20 ml) and extracted with ethyl acetate (2×20 ml). The combinedorganic extracts were washed with aqueous 2% citric acid (20 ml), water(20 ml), saturated sodium bicarbonate (20 ml), saturated brine (20 ml),dried (Na₂SO₄) and solvents removed in vacuo to leave a straw colouredoil. This crude product was the purified by silica gel columnchromatography, eluting with a gradient of 2% diethyl ether indichloromethane rising to 4% diethyl ether in dichloromethane, tofurnish the title compound as a colourless oil (0.29 g, 44%).

[0183] TLC R_(f) 0.31 (4% diethyl ether/dichloromethane)

[0184] MS: 372 (MH⁺)

Example 20 2-(Piperidin-4-ylsulfanyl)cyclopentanecarboxylic acid methylester

[0185] Methyl 1-cyclopentene-1-carboxylate (0.24 ml) and Intermediate 12(0.50 g) were dissolved in anhydrous methanol (20 ml), degassed withnitrogen, and cooled to −10 to −15° C. Sodium bis(trimethylsilyl)amide,1.0 M in tetrahydrofuran (1.93 ml) was added and the reaction stirredfor 18 h, warming to room temperature. The reaction mixture was thenevaporated and the residue partitioned between ethyl acetate (20 ml) andwater (20 ml). The aqueous was extracted once more with ethyl acetate(10 ml) and the combined organic extracts were washed with 2% aqueouscitric acid (20 ml), water (20 ml), saturated sodium bicarbonate (20ml), saturated brine (20 ml), dried (Na₂SO₄) and evaporated underreduced pressure.

[0186] The resultant amber oil was dissolved in dichloromethane (10 ml)and treated with trifluoroacetic acid (2 ml). After stirring at roomtemperature for 17 h, the solvents were evaporated and the residueazeotroped with 1:1 dichloromethane/hexane (3×20 ml). The residue wasthen dissolved in water (30 ml) and washed with diethyl ether (2×10 ml)before being basified with sodium carbonate to pH 11 and extracted withethyl acetate (4×15 ml). The combined ethyl acetate extracts were thenwashed with saturated brine (10 ml), dried (Na₂SO₄) and reduced in vacuoto provide the title compound as a colourless gum (0.15 g, 31%).

[0187] TLC R_(f) 0.26 (6% methanol/dichloromethane containing a trace ofaqueous ammonia)

[0188] MS 244 (MH⁺)

Example 21 1-(Piperidin-4-ylsulfanylmethyl)cyclohexanecarboxylic acidmethyl ester

[0189] Example 19 (0.28 g) was dissolved in dichloromethane (10 ml) andtreated with trifluoroacetic acid (2 ml). The solution was stirred atroom temperature for 5 h, then evaporated under reduced pressure, andthe residue azeotroped with 1:1 dichloromethane/hexane (2×20 ml). Theresultant gum was then dissolved in water (30 ml) and washed withdiethyl ether (2×10 ml), back-extracting the organic washes with aqueous1% citric acid (2×5 ml). The aqueous phase was then basified withpotassium carbonate to pH 11/12, saturated with solid sodium chloride,and extracted with ethyl acetate (4×10 ml). The combined organicextracts were washed with saturated brine (10 ml), dried (Na₂SO₄) andreduced under vacuum to give the title compound as a colourless gum(0.19 g, 92%).

[0190] TLC R_(f) 0.25 (6% methanol/dichloromethane containing a trace ofaqueous amnmonia)

[0191] MS: 272 (MH⁺)

Example 222-[1-(4-Cyanophenyl)piperidin-4-ylsulfanyl]cyclopentane-carboxylic acidmethyl ester

[0192] Example 20-(0.143 g), 4-fluorobenzonitrile (0.142 g) andpotassium carbonate (0.081 g) were combined in anhydrousN,N-dimethylformamide (10 ml) and heated to 100° C. for 3 h, undernitrogen. After cooling, the reaction mixture was poured onto water (100ml) and extracted with ethyl acetate (2×30 ml). The organic extractswere then washed with water (2×20 ml), aqueous 1% citric acid (30 ml),water (10 ml), saturated sodium bicarbonate (20 ml), saturated brine (20ml), dried (Na₂SO₄) and evaporated to dryness. The residue was purifiedby silica gel column chromatography with 1:1 hexane/diethyl ether aseluent to furnish the title compound as a colourless gum (0.036 g, 18%).

[0193] TLC R_(f) 0.44 (1:1 hexane/diethyl ether)

[0194] MS: 345 (MH⁺)

[0195] The following compounds were prepared in a similar manner:

Example 231-[1-(4-Nitrophenyl)piperidin-4-ylsulfanylmethyl]cyclo-hexanecarboxylicacid methyl ester

[0196] Prepared in the same manner as Example 22 from Example 21 (0.19g) and 1-fluoro-4-nitrobenzene (0.20 g), with 1-methyl-2-pyrrolidinone(10 ml) as solvent, to yield the title compound as a yellow gum (0.25 g,91%).

[0197] TLC R_(f) 0.33 (3:2 hexane/diethyl ether)

[0198] MS 393 (MH⁺)

Example 24 2-[1-(4-Cyanophenyl)piperidin-4-ylsulfanyl]cyclopentane-carboxylic acid

[0199] Lithium hydroxide monohydrate (0.022 g), as a solution in water(3 ml), was added dropwise to a stirred solution of Example 22 (0.036 g)in dioxane, held at just above its freezing point in an ice/sodiumchloride bath. The mixture was then stirred in the ice bath, slowlywarming to room temperature over 3 h. The reaction mixture was thenreduced under vacuum, and the residue diluted with water (10 ml) andwashed with diethyl ether (2×10 ml), back-extracting the ether washeswith dilute sodium bicarbonate solution (2×5 ml). The aqueous phase wasthen acidified with citric acid to pH 4/5 and extracted with ethylacetate (3×10 ml). The combined ethyl acetate extracts were washed withwater (2×10 ml), saturated brine (10 ml), dried (Na₂SO₄) and reduced invacuo to give the title compound as a colourless gum ( 0.035 g, 100%)

[0200] TLC R_(f) 0.39 (1:1 ethyl acetate/hexane)

[0201] MS 331 (MF⁺)

Example 251-[1-(4-Nitrophenyl)piperidin-4-ylsulfanylmethyl]cyclohexane-carboxylicacid

[0202] Example 23 (0.24 g) and lithium hydroxide monohydrate (0.13 g)were combined in tetrahydrofuran (10 ml), methanol (5 ml) and water (2.5ml) and heated to reflux for 7 h. The reaction was then cooled andreduced under vacuum. The residue was diluted with water (40 ml) andwashed with ethyl acetate (2×20 ml), back-extracting with dilute sodiumbicarbonate (2×10 ml). The combined aqueous phase was then acidifiedwith citric acid to pH 4 and extracted with ethyl acetate (2×20 ml). Thecombined ethyl acetate extracts were washed with water (2×10 ml),saturated brine (20 ml), dried (Na₂SO₄) and reduced under vacuum toprovide the title compound as a yellow solid (0.083 g, 35%).

[0203] TLC R_(f) 0.45 (1:1 hexane/ethyl acetate)

[0204] MS 379 (MH⁺)

Example 261-[1-(4-Nitrophenyl)piperidine-4-sulfinylmethyl]cyclohexane-carboxylicacid

[0205] Oxone (0.133 g) was dissolved in water (10 ml) and added to asolution of Example 25 (0.083 g) in methanol (10 ml), cooled in anice/salt bath. The resultant suspension was vigorously stirred for 3days, warming to room temperature. The reaction mixture was then dilutedwith water (35 ml) and extracted with dichloromethane (3×15 ml). Thecombined organic extracts were washed with water (10 ml), saturatedbrine (10 ml), dried (Na₂SO₄) and reduced in vacuo to leave a yellowsolid which was triturated with several small portions ofdichloromethane to provide the title compound as a yellow solid (0.049g, 56%)

[0206] TLC R_(f) 0.30 (5% methanol/dichloromethane)

[0207] MS 379 (MF⁺)

Example 274-((3-(4-Chlorophenoxy)propylsulfonyl)methyl)tetrahydro-pyran-4-carboxylicacid N-hydroxy amide

[0208] EDC (40 mg) was added to a solution of Example 13 (75 mg) indichloromethane (20 ml), followed bytert-butyldimethylsilylhydroxylamine (32 mg) andN,N-dimethylaminopyridine (2 mg), and the resulting clear solution wasstirred at room temperature for 3 h. The mixture was then washed withwater, saturated bicarbonate and brine, dried over MgSO₄ and evaporated.The residue was dissolved in a minimum amount of fresh dichloromethaneand IM aqueous hydrochloric acid in ether (2 ml) was added. The solutionwas stirred for 10 min, then evaporated and the residue purified bychromatography on silica, eluting with ethyl acetate, to give the titlecompound (30 mg) as a colourless glass.

[0209] TLC R_(f) 0.27 (EtOAc)

[0210] MS 391 (M⁺)

Example 284-((3-(4-Methoxyphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylicacid N-hydroxy amide

[0211] To a stirred solution of Example 14 (250 mg) in dichloromethane(15 ml) containing a drop of DMF was added oxalyl chloride (256 mg). Themixture was stirred for 1 h before removing the solvent under reducedpressure. The residue was treated three times with a mixture ofdichloromethane/hexane (1:1; 50 ml) and evaporated to dryness. Theresidue was dissolved in THF (15 ml) and treated with an aquoeussolution of hydroxylamine (50 wt %; 0.21 ml). The mixture was stirredfor 1 h before diluting with water (10 ml) and extracting with ethylacetate (3×10 ml). The combined ethyl acetate extracts were washed withsaturated sodium bicarbonate solution (20 ml), water (20 ml), brine (20ml), dried over MgSO₄ and evaporated to yield the title compound (145mg) as a colourless solid.

[0212] TLC R_(f) 0.60 (9:1 dichloromethane/methanol)

[0213] MS 387 (M⁺)

[0214] Similarly prepared was:

Example 294-((3-(4-Phenylphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylicAcid N-hydroxy amide

[0215] From Example 15 (180 mg) as a white solid (124 mg).

[0216] TLC R_(f) 0.42 (9:1 dichloromethane/methanol)

[0217] MS 433 (M⁺)

Example 301-{2-[1-(4-Nitrophenyl)pyrrolidin-3-yl]-ethanesulfonylmethyl}-cyclobutanecarboxylicacid hydroxyamide

[0218] Prepared in the same manner as Example 28 from Example 17 (75mg), oxalyl chloride (0.06 ml) and hydroxylamine (50% in water, 0.06 ml)to give Example 31 (66 mg) as a yellow solid.

[0219] TLC R_(f) 0.35 (5% methanol in dichloromethane)

[0220] MS 412 (MH⁺)

Example 31 2-(3-Phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acidhydroxyamide

[0221] Prepared in the same manner as Example 28 from Example 18 (121mg), oxalyl chloride (0.135 ml) and hydroxylamine (50% in water, 0.12ml) to give the title compound (84 mg) as a white solid.

[0222] TLC R_(f) 0.29 (5% methanol in dichloromethane)

[0223] MS 328 (MH⁺)

We claim:
 1. A compound of formula (I)B—S(O)₀₋₂—(CH₂)₀₋₁—CR²R³—CR⁴R⁵—COY   (I)wherein Y is selected from thegroup consisting of OR¹ and NHOH; R² and R⁴ are independently selectedfrom the group consisting of H and a moiety (optionally substituted withR¹⁰) selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, heterocycloalkyl, C₁₋₆alkyl-heterocycloalkyl, cycloalkyl and C₁₋₆ alkyl-cycloalkyl; R¹ and R³and R⁵ are independently selected from the group consisting of H andC₁₋₆alkyl; provided that not more than two of R², R³, R⁴ and R⁵ are H;or any of CR²R³, CR⁴R⁵ and CR²—CR⁴ is a cycloalkyl or heterocycloalkylring optionally substituted with R¹⁰ or a group (optionally substitutedwith R¹⁰) selected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryland C₁₋₆ alkyl-heteroaryl; B is selected from the group consisting ofC₁₋₈ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl, and is substituted with R⁶; Ris selected from the group consisting of N(R⁷)₂, OR⁷, COR⁷, C(═NOR⁹)R⁷,NR⁷R⁸, S(O)₀₋₂,R⁹, and SO₂N(R⁷)₂; R⁷ is selected from the groupconsisting of H and a moiety selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl,wherein said moiety is optionally substituted with R⁹, COR⁹, SO₀₋₂R⁹,CO₂R⁹, OR⁹, CONR¹R⁹, NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂, and for eachcase of N(R⁷)₂ the R⁷ groups are the same or different, or N(R⁷)₂ isheterocycloalkyl optionally substituted with R⁹, COR⁹, SO₀₋₂R⁹, CO₂R⁹,OR⁹, CONR¹R⁹, NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂; R⁸ is selected fromthe group consisting of COR⁷, CON(R⁷)₂, CO₂R⁹ and SO₂R⁹; R⁹ is selectedfrom the group consisting of C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl and C₁₋₆ alkyl-heteroaryl; and R¹⁰ is selected from the groupconsisting of OR⁷, COR⁷, CO₂R¹, CON(R⁷)₂, NR⁷R⁸, S(O)₀₋₂R⁹, SO₂N(R⁷)₂,CN, halogen and cycloimidyl (optionally substituted with R¹); or a salt,solvate, hydrate, N-oxide or protected amino, protected carboxy orprotected hydroxamic acid derivative thereof.
 2. The compound of claim1, wherein R² or R⁴ is optionally substituted C₁₋₆ alkyl, C₁₋₆alkyl-heteroaryl, or C₁₋₆ alkyl-heterocycloalkyl; or CR²R³, CR⁴R⁵ orCR²—CR⁴ forms the said optionally substituted ring.
 3. The compound ofclaim 1, wherein B is C₁₋₈ alkyl substituted with R⁶.
 4. The compound ofclaim 3, wherein B is C₁₋₈ alkyl substituted with OR⁷.
 5. The compoundof claim 4, wherein R⁷ is optionally substituted aryl or heteroaryl. 6.The compound of claim 1, wherein S(O)₀₋₂ is SO₂.
 7. The compound ofclaim 1, selected from the group consisting of methyl4-((3-(3-pyridyloxy)propylsulfanyl)methyl)tetrahydropyran-4-carboxylate,methyl4-((3-(3-pyridyloxy)propylsulfonyl)methyl)tetrahydropyran-4-carboxylate,and4-((3-(4-pyridyloxy)propylsulfonyl)methyl)tetrahydropyran-4-carboxylate.8. The compound of claim 1, selected from the group consisting of2-(3-phenoxypropylsulfanyl)cyclopentanecarboxylic acid methyl ester,2-(3-phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid methyl ester,2-(3-phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid and2-(3-phenoxypropane-1-sulfonyl)cyclopentanecarboxylic acid hydroxyamide.9. A pharmaceutical composition for the use in therapy, comprising acompound of claim 1, and a pharmaceutically-acceptable diluent orcarrier.
 10. A method for the treatment of a condition selected from thegroup consisting of asthma, inflammation, inflammatory diseases,autoimmune, infectious or ocular diseases, age-related maculardegeneration, and cancer, which comprises administering to a subject inneed thereof an effective amount of a compound of claim
 1. 11. Acompound of formula (I) B—S(O)₀₋₂—(CH₂)₀₋₁—CR²R³—CR⁴R⁵—COY   (I) whereinY is selected from the group consisting of OR¹ and NHOH; R² and R⁴ areindependently selected from the group consisting of H and a moiety(optionally substituted with R¹⁰) selected from C₁₋₆ alkyl, C₁₋₆alkenyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,heterocycloalkyl, C₁₋₆ alkyl-heterocycloalkyl, cycloalkyl and C₁₋₆alkyl-cycloalkyl; R¹, R³ and R⁵ are independently selected from thegroup consisting of H and C₁₋₆ alkyl; provided that not more than two ofR², R³, R⁴ and R⁵ are H; or any of CR²R³, CR⁴R⁵ and CR²-CR⁴ is acycloalkyl or heterocycloalkyl ring optionally substituted with R¹⁰ or agroup (optionally substituted with R¹⁰) selected from C₁₋₆ alkyl, aryl,C₁₋₆ alkyl-aryl, heteroaryl and C₁₋₆ alkyl-heteroaryl; B is C₁₋₆alky-heterocycloalkyl group optionally substituted with R⁶ or R⁷; R⁶ isselected from the group consisting of N(R⁷)₂, OR⁷, COR⁷, C(═NOR⁹)R⁷,NR⁷R⁸, S(O)₀₋₂R⁹ and SO₂N(R⁷)₂; R⁷ is selected from the group consistingof H and a moiety selected from C₁₋₆ alkyl, aryl, C₁₋₆ alky-aryl,heteroaryl, C₁₋₆ alky-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl, wherein said moiety isoptionally substituted with R⁹, COR⁹, SO₀₋₂R⁹, CO₂R⁹, OR⁹, CONR¹R⁹,NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂, and for each case of N(R⁷)₂ the R⁷groups are the same or different, or N(R⁷)₂ is heterocycloalkyloptionally substituted with R⁹, COR⁹, SO₀₋₂R⁹, CO₂R⁹, OR⁹, CONR¹R⁹,NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂; R⁸ is selected from the groupconsisting of COR⁷, CON(R⁷)₂, CO₂R⁹ and SO₂R⁹; R⁹ is selected from thegroup consisting of C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl andC₁₋₆ alkyl-heteroaryl; and R¹⁰ is selected from the group consisting ofOR⁷, COR⁷, CO₂R¹, CON(R⁷)₂, NR⁷R⁸, S(O)₀₋₂R⁹, SO₂N(R⁷)₂, CN, halogen andcycloimidyl (optionally substituted with R¹); or a salt, solvate,hydrate, N-oxide or protected amino, protected carboxy or protectedhydroxamic acid derivative thereof.
 12. The compound of claim 11,wherein R² or R⁴ is optionally substituted C₁₋₆ alkyl, C₁₋₆alkyl-heteroaryl, or C₁₋₆ alkyl-heterocycloalkyl; or CR²R³, CR⁴R⁵ orCR²—CR⁴ forms the said optionally substituted ring.
 13. The compound ofclaim 11, wherein the alkyl group in B is selected from the groupconsisting of ethyl and propyl.
 14. The compound of claim 11, whereinthe heterocycloalkyl group in B is selected from the group consisting ofazetidinyl, pyrrolidinyl and piperdinyl, aryl which is substituted withR⁷.
 15. The compound of claim 14, wherein R⁷ is optionally substitutedaryl or heteroaryl.
 16. The compound of claim 11, wherein S(O)₀₋₂ isSO₂.
 17. The compound of claim 11, selected from the group consisting of1-{2-[1-(4-nitrophenyl)pyrrolidin-3-yl]ethylsulfanylmethyl}cyclobutanecarboxylicacid ethyl ester,1-{2-[1-(4-nitrophenyl)pyrrolidin-3-yl]ethanesulfonylmethyl}cyclobutanecarboxylicacid ethyl ester,1-{2-[1-(4-nitrophenyl)pyrrolidin-3-yl]ethanesulfonylmethyl}cyclobutanecarboxylicacid and 2-(piperidin-4-ylsulfanyl)cyclopentanecarboxylic acid methylester.
 18. A pharmaceutical composition for use in therapy, comprising acompound of claim 11, and a pharmaceutically-acceptable diluent orcarrier.
 19. A method for the treatment of a condition selected from thegroup consisting of asthma, inflammation, inflammatory diseases,autoimmune, infectious or ocular diseases, age-related maculardegeneration, and cancer, which comprises administering to a subject inneed thereof an effective amount of a compound of claim
 11. 20. Acompound of formula (I) B—S(O)₀₋₂—(CH₂)₀₋₁—CR²R³—CR⁴R⁵—COY   (I) whereinY is selected from the group consisting of OR¹ and NHOH; R² and R⁴ areindependently selected from the group consisting of H and a moiety(optionally substituted with R¹⁰) selected from C₁₋₆ alkyl, C2-6alkenyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,heterocycloalkyl, C₁₋₆ alkyl-heterocycloalkyl, cycloalkyl and C₁₋₆alkyl-cycloalkyl; R¹, R³ and R⁵ are independently selected from thegroup consisting of H and C₁₋₆ alkyl; provided that not more than two ofR², R³, R⁴ and R⁵ are H; or any of CR²R³, CR⁴R⁵ and CR²-CR⁴ is acycloalkyl or heterocycloalkyl ring optionally substituted with R¹⁰ or agroup (optionally substituted with R¹⁰) selected from C₁₋₆ alkyl, aryl,C₁₋₆ alkyl-aryl, heteroaryl and C₁₋₆ alkyl-heteroaryl; B isheterocycloalkyl, optionally substituted with R⁶ or R⁷, bonded through aC atom to S(O)₀₋₂. R⁶ is selected from the group consisting of N(R⁷)₂,OR⁷, COR⁷, C(═NOR⁹)R⁷, NR⁷R⁸, S(O)₀₋₂R⁹ and SO₂N(R⁷)₂; R⁷ is selectedfrom the group consisting of H and a moiety selected from C₁₋₆ alkyl,aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alky-heteroaryl, cycloalkyl,C₁₋₆ alky-cycloalkyl, heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl,wherein said moiety is optionally substituted with R⁹, COR⁹, SO₀₋₂R⁹,CO₂R⁹, OR⁹, CONR¹R⁹, NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂, and for eachcase of N(R 7)₂ the R⁷ groups are the same or different, or N(R⁷)₂ isheterocycloalkyl optionally substituted with R⁹, COR⁹, SO₀₋₂R⁹, CO₂R⁹,OR⁹, CONR¹R⁹, NR¹R⁹, halogen, CN, SO₂NR¹R⁹ or NO₂; R⁸ is selected fromthe group consisting of COR⁷, CON(R⁷)₂, CO₂R⁹ and SO₂R⁹; R⁹ is selectedfrom the group consisting of C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl and C₁₋₆ alky-heteroaryl; and R¹⁰ is selected from the groupconsisting of OR⁷, COR⁷, CO₂R¹, CON(R⁷)₂, NR⁷R⁸, S(O)₀₋₂R⁹, SO₂N(R⁷)₂,CN, halogen and cycloimidyl (optionally substituted with R¹); or a salt,solvate, hydrate, N-oxide or protected amino, protected carboxy orprotected hydroxamic acid derivative thereof.
 21. The compound of claim20, wherein R² or R⁴ is optionally substituted C₁₋₆ alkyl, C₁₋₆alkyl-heteroaryl, or C₁₋₆ alkyl-heterocycloalkyl; or CR²R³, CR⁴R⁵ orCR²—CR⁴ forms the said optionally substituted ring.
 22. The compound ofclaim 20, wherein B is selected from the group consisting of azetidinyl,pyrrolidinyl and piperidinyl, any of which is substituted with R⁷. 23.The compound of claim 22, wherein R⁷ is optionally substituted aryl orheteroaryl.
 24. The compound of claim 20, wherein S(O)₀₋₂ is SO₂. 25.The compound of claim 20, selected from the group consisting of4-(1-methoxycarbonylcyclohexylmethylsulfanyl)piperidine- 1-carboxylicacid tert-butyl ester, 2-(piperidin-4-ylsulfanyl)cyclopentanecarboxylicacid methyl ester, 1-(piperidin-4-ylsulfanylmethyl)cyclohexanecarboxylicacid methyl ester,2-[1-(4-cyanophenyl)piperidin-4-ylsulfanyl]cyclopentane-carboxylic acidmethyl ester,1-[1-(4-nitrophenyl)piperidin-4-ylsulfanylmethyl]cyclohexanecarboxylicacid methyl ester,2-[1-(4-cyanophenyl)piperidin-4-ylsulfanyl]cyclopentanecarboxylic acid,1-[1-(4-nitrophenyl)piperidin-4-ylsulfanylmethyl]cyclohexanecarboxylicacid and1-[1-(4-nitrophenyl)piperidin-4-ylsulfinylmethyl]cyclohexanecarboxylicacid.
 26. A pharmaceutical composition for use in therapy, comprising acompound of claim 20, and a pharmaceutically-acceptable diluent orcarrier.
 27. A method for the treatment of a condition selected from thegroup consisting of asthma, inflammation, inflammatory diseases,autoimmune, infectious or ocular diseases, age-related maculardegeneration, and cancer, which comprises administering to a subject inneed thereof an effective amount of a compound of claim 20.